In a series of studies, we and others have found that patients with schizophrenia have relatively reduced metabolic rates in their frontal cortex, temporal lobe and basal ganglia when assessed with positron emi- ssion tomography with 18-F 2-deoxyglucose (FDG). We propose to identify and validate subtypes of schizophrenia based on functional neuroanatomy of these three regions. We will refine our image analysis routines using our MRI template method, assess the accuracy with our new anatomically accurate brain phantom method, replicate findings of a relationship between basal ganglia metabolic rate and neuroleptic response, trace longitudinal change and evaluate familial effects. In Experiment 1, 40 patients with schizophrenia will participate in a 10-week trial of a standard neuroleptic; the design will be a double-- blind, random assignment crossover with PET scans after each five-week period. We will enlarge our current sample of 30 never-medicated patients, and enter as many as possible into the drug trial. In Experiment 2, we will rescan subjects at a five-year followup and evaluate developmental effects with a study of psychotic adolescents and an age-matched depression control group. In Experiment 3, we will scan the siblings of 24 patients with schizophrenia to evaluate familial effects. Patients in all experiments will be evaluated clinically with an expanded life-time version of the Present State Exam structured interview, diagnosed by DSM-III-R criteria, and screened for medical illness. Urine testing will verify drug status. Subjects will perform the degraded Continuous Performance Test during FDG uptake. Following uptake of FDG, the scanner (7.6 mm in plane and 11.6 mm axial resolution) will obtain slice images in micromoles glucose/l00g/ minute. All subjects will receive MRI scans at 5 mm intervals, using the same individually fitted, thermoplastic head holder to allow specific structures to be identified by reference to the anatomic image. Computer algorithms for tracing the caudate, putamen, and other regions will be employed to yield PET templates as well as size and shape assessments.